The present invention relates to nitroheteroaryl-substituted rifamycin derivatives wherein a nitroimidazole, nitrothiazole or nitrofuran pharmacophore is chemically combined with a rifamycin. The present invention also relates to a method of preparing pharmacologically active rifamycin derivatives and various intermediates used in the method. The inventive rifamycin derivatives are useful as antimicrobial agents effective against a number of human and veterinary aerobic and anaerobic Gram positive, Gram negative pathogens, including the Staphylococci, for example S. aureus; Enterococci, for example E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia for example E. coli; Mycobacteria, for example M. tuberculosis; Helicobacter, for example H. pylori; Clostridium, for example C. difficile; Bacteroides for example, B. fragilis, B. vulgates; intercellular microbes, for example Chlamydia and Rickettsiae; and Mycoplasma, for example M. pneumoniae, amongst others.
The rifamycin derivatives may be used as agents effective against GI disorders including travelers' and infectious diarrhea (E. coli, Salmonella and Shigella), hepatic encephalopathy, Crohn's disease, ulcerative colitis, irritable bowel syndrome, pouchitis, small-bowel bacterial overgrowth, peptic ulcer disease due to H. pylori, and diverticular disease. The present compounds also are cytotoxic anticancer agents, antifungal agents, and antiprotozoal agents (against, for example, entamoeba histolyica, and Neglaria sps). The present invention also relates to pharmaceutical compositions containing the inventive rifamycin derivatives, to methods of treating a bacterial infection using the rifamycin derivatives.
The increase in bacterial resistance to existing antibacterial agents is a major clinical problem. Accordingly, there is a need in the art for compounds, compositions, and methods of treating warm-blooded animals that suffer from a bacterial infection and are resistant to conventional antibacterial treatments. Rifamycin class of natural product derived antibiotics, like rifampin, rifabutin and rifapetine are currently used for the treatment of tuberculosis and other microbial infections (Farr, B. M. Rifamycins, in Principles and Practice of Infectious Diseases; Mandell, G. L., Bennett, J. E., Dolin, R., Eds.; Churchhill Livingstone: Philadelphia; p. 348-361). At present, one of the major problems associated with the rifamycin class of antimicrobial agents is the rapid development of bacterial resistance. Mutations in rifamycin's antibacterial target RNA polymerase are mainly responsible for the high frequency of development of resistance. Consequently, rifamycins are currently used only in combination therapies to minimize the development of resistance to this class of drug. Unfortunately, even with co-administration of other antibiotics, resistance development to rifamycins is frequent in the clinic (Chaisson, R. E. “Treatment of chronic infections with rifamycins: is resistance likely to follow?”, Antimicrob. Agents & Chemother. 47(10): p. 3037-39 (2003)).
Nitroimidazoles, nitrothiazoles and nitrofurans classes of antibiotics are well-known antibacterials against anaerobic bacteria. A member of nitroimidazole class is metronidazole (U.S. Pat. No. 2,944,061), which is presently prescribed as antiprotozoal (for treatment of Trichomonas infections). Metronidazole is also clinical used for treatment of anaerobic bacterial infections due to Clostridium and Bacteroides species. Nitazoxanide (U.S. Pat. No. 3,950,351) is a nitrothiazole compound is being used for treatment of diarrhea caused by Cryptosporidium parvum. Nitrofurantoin (U.S. Pat. No. 2,610,181) is a member of nitrofuran class, which is being used for treatment of acute urinary tract infections. Recently a new member of nitroimidazole class of compounds 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines (U.S. Pat. No. 6,087,358) described in structure (1) below were disclosed as antibacterials, wherein R1 and R2 are substituted or unsubstituted alkyls, aryls, alkyloxy or aryloxy; X is O, S, NR2 etc.; Y, Z are CH2, CHR2 and heteroatoms etc. In addition, new nitroimidazole derivatives 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles (WO 2005/042542 A1) described in structure (2) below were disclosed as agents for the treatment of tuberculosis, wherein R1 represents H, alkyls etc.; R2 is alkoxy, aryloxy, substituted aryloxy etc.

Although rifamycins, nitroimidazoles, nitrothiazoles, and nitrofurans are known, there is no reference that discloses covalently bonding a rifamycin to a nitroimidazole, a nitrothiazole or a nitrofuran and using the resulting rifamycin derivatives as anti-bacterial agents against both aerobic and anaerobic Gram-positive and negative bacteria, and defeat resistance to rifamycin.
Syntheses of simple rifamycin derivatives is well known in the art, for example, the synthesis of rifampin (U.S. Pat. No. 3,342,810), rifabutin (U.S. Pat. No. 4,219,478), and rifalazil (U.S. Pat. No. 4,983,602) are known in the art and disclosed. However, the synthesis of a rifamycin covalently linked to a nitroimidazole, a nitrothiazole or a nitrofuran is not straightforward. Thus, a method of synthesizing compounds of the present invention has not been publicized.